Acyl substituted phenyl alkanoic acids

ABSTRACT

where R and R&#39;&#39; are independently selected from the group consisting of aryl, alkyl, cycloalkyl or substituted derivatives thereof and x is an integer of from 1 to 3. These novel compounds may be exemplified by bis-(N-methyl-p-toluenesulfonamido)disulfide.   Novel compounds for inhibiting the premature vulcanization of vulcanizable rubber formulations comprising bis-(sulfonamido)sulfides or polysulfides having the formula:

United States Patent Houlihan et al. Nov. 11, 1975 [54] ACYL SUBSTITUTEDPHENYL [56] References Cited ALKANOIC ACIDS [75] Inventors: William J.Houlihan, Mountain UNITED STATES PATENTS k i Jefireby f z ff' Lake3,228,831 1/1966 Nicholson et al .260/515 arslPPanY, 2,980,732 4/1961Girard et al ..260/5 15 [73] Assignee: Sandoz, Inc., E. Hanover, NJ2385,404 5/1959 Petrow et a1 ..260/5l5 3,352,901 11/1967 Schultz et al..260/515 [22] Filed: Mar. 19, 1973 P P rimary ExaminerJames A. atten[21] Appl 342463 Attorney, Agent, or FirmGerald D. Sharkin et al.

Related U.S. Application Data [57] ABSTRACT Commuauon-m-part of Ser. No.281.916, Aug. 18,

abandoned Acyl substituted phenyl alkanoic acids, e.g. p-pivaloyl [1.8.CI. R, F, G, phenyl acetic acid are prepared hydrolyzing p 260/ 515Aim/521 260/592; 424/317 pivaloyl phenyl acetonitriles and are useful ashypo- [51] Int. GL ..C07C 65/20 pidemic agents [58] FieldofSearch..260/5l5 R, 521 R, 515 A 9 Claims, No Drawings This application is acontinuation-in-part of application Ser. No. 281,916, filed Aug. 18,1972, now

where R R R R and R are as set out above.

The compounds of formula (I) are prepared by hydrolyzing compounds offormula (11) with aqueous mineral acids. When R is hydrogen or halo, itis abandoned. 5 preferred that concentrated mineral acid be used.

This application relates to acyl substituted phenyl When R, is loweralkoxy, it is preferred that a dilute alkanoic acids which exhibithypolipidemic activity. mineral acid be employed. The acid can be hydro-In particular, it relates to substituted phenyl alkanoic chloric acid,sulfuric acid, phosphoric acid and the acids,pharmaceutically acceptablesalts, their prepara like. The particular acid used is not critical buttion and intermediates thereof. hydrochloric acid is preferred. Theaqueous solvent The compounds of this invention may be reprecan be wateror a mixture of water and a water soluble sented by the formula: organicsolvent, e.g., the lower alkanols. The preferred solvent is water,although the particular solvent used :2 is not critical. The temperatureof the reaction is R -C- 15 also not critical, but it is preferred thatthe reaction be carried out at the reflux temperature of the solvent. R(I) For optimum results the reaction is run for about 12 3 to 72 hours,preferably 40 to 50 hours. The product is recovered by conventionaltechniques, e.g., re- C= crystallization. The compounds of formula (1])where R and R CH -C-R 3 I each represent lower alkyl are preparedaccordmg to 5 the following reaction scheme:

R -CH-CN R1 6 CN c=o base i= I t CH -C-R cu -ci-a 3 I h R R 5 (II') 5where 40 where R, and R, are each independently lower alkyl,

R, and R each independently, represent hydrogen n 1, 3, R4 and 5 e as eOut above. Provided or lower alkyl having 1 to 2 carbon atoms, i.e. thatwhen R. is hydrogen, R, and R; each represent methyl or ethyl, and thesame lower alkyl.

R3 represents hydrogen, halo having an atomic T e Compounds of formulaare pf p j y weight of about 19 to 36, and straight chain reactlllg acompound of the fOfmllla Wllh an lower alkoxy, i.e., straight chainalkoxy having alkyl iodide such as methyliodide in the presence of 1 to4 carbon atoms e.g methoxy ethoxy, i an inorganic base and an inertorganic solvent. Suitpropoxy, or the like, and able strong bases whichmay be employed include the R and R each independently, represent lk lalkali metal amides such as postassium amide and the h i 1 g carbonatoms alkali metal hydrides such as sodium hydride or The compounds offormula (I) are prepared accord- Potassium y pfmlcular base used 15 noti to h f ll i reaction h critical but sodium amide is preferred. Thepreferred R -C-C0 H mineral acid 5 R F CH -f-R R solvents aredimentylacetamide, tetrahydrofuran, inorganic peroxide, especiallybenzoyl peroxide. The ether or liquid ammonia, the latter beingespecially reaction can also be carried out under ultraviolet light.preferred. The temperature of the reaction is not Although theparticular solvent used is not critical, the critical, but it ispreferred that the reaction be carried preferred solvents are thehalogenated hydrocarbons out between about 100 to 50C., especially 80 5such as methylene dichloride, chloroform, carbon tetto about -70C. Thereaction is run from about 1 to rachloride and the like. although thearomatic hydro- 6 hours, preferably from about 2.5 to 3.5 hours. Thecarbons such as benzene can also be employed. The product is recoveredusing conventional techniques, temperature of the reaction is notcritical. but reflux e.g. filtration. temperature of the solvent ispreferred. For optimum The compounds of formula (II) can be preparedresults. the reaction is run for about 12 to 48 hours; according to thefollowing reaction scheme: preferably l8 to 25 hours. The product isrecovered L' a -Cl -CN 3 MCN c=o CH 3 cu -i:-R

5 (III) B (II' where M represents an alkali metal. preferably sodium byconventional techniques, e.g., crystallization. or potassium and R R R4and R5 are as set out Many of the compounds of formula [V are knownabove. and may be prepared by methods described in the The compounds offormula (ll') are prepared by literature. The compounds of formula IVnot specifitreating compounds of formula (lll) with an alkali callydisclosed may be prepared by analogous methods metal cyanide such assodium cyanide, potassium from known starting materials. cyanide. andthe like. preferably potassium cyanide, The compounds of formula(l) areuseful because in the presence of an aqueous organic solvent. The theypossess pharmacological activity in animals, preferred solvents are theaqueous-lower alkanols particularly as hypolipidemic agents and thecomsuch as water and methanol. ethanol and the like, pounds areespecially useful as hypocholesterolemic and water-dioxane. althoughanhydrous dimethyland hypotriglyceridemic agents as indicated by thesulfoxide can also be employed. The temperature of fall in Cholesiemiand triglyceride levels ill male the reaction is not critical but it ispreferred that albino wislar rats weighing initiallythe process becarried out at a temperature between The rats are maimaimid drug-freelaboralflry chow about to [20C, especially the reflux temperature dietfor seven days and then divided into groups of of the system. Foroptimum results. the reaction is 8 I0 10 animals- Each group with theexception of run for about 1-10 hours; preferably 3 to 5 hours. theControl is given y 30 milligrams P The product is recovered byconventional techniques, 40 kilogram of body weight per diem of thecompound e.g..evaporation. for six days. At the end of this period. theanimals The I compounds of formula (Ill) are prepared are anesthetizedwith sodium hexobaribital and bled according to the following reactionscheme: from the carotid arteries. Serum or plasma samples R -CH-Br R-CH 1 R brominating agent 5 C=O i= 1 CH -C-R ca e-a 3 i (IV) (III) whereR.. R3. R4, and R,-, are as set out above. are collected, and 1.0 mlsamples of the serum are The compounds of formula (III) are prepared byadded to 9.0 ml redistilled isopropanol. Two autotreating a compound offormula(lV) withabrominatanalyzer of cupsful of a mixture ofzeolite-copper ing agent in the presence of an inert organic solventhydroxide and Lloydds reagent (Kessler, G., and and free radicalinitiator. The brominating agent Lederer, 11., I965, TechniconSymposium, Mediad which can be used is bromine,N-bromosuccinimide, Inc.,New York, (345-347)) are added, and the N-bromo phthalamide,N-bromo-acetamide and the mixture is shaken for one hour. Cholesteroland like. The particular agent used is not critical, but triglyceridelevels are determined simultaneously N-bromocuccinamide is preferred. inthe preferred on the same sample by Technicon N 24 A process, the freeradical initiator used is an organic or terol) and N-78 (triglyceride)methodology. The

mean total serum cholesterol levels are then computed and thehypocholesterolemic activity is expressed as the fall in cholesterollevels as a percentage of the control level. The change in serumtrigylceride levels induced by the dmg is computed as a percentage ofthe control triglyceride levels.

For such usage, the compounds (I) may be combined with apharmaceutically acceptable carrier or adjuvant and may be administeredorally or parenterally as such or admixed with conventionalpharmaceutical carriers. They may be administered in such forms astablets, dispersible powders, granules, capsules, syrups and elixirs andparenterally as solutions, suspensions, dispersions, emulsions and thelike, e.g., a sterile injectable aqueous solution. The dosage will varydepending upon the mode of administration utilized and the particularcompound employed.

The compounds of formula (1) may be similarly administered in the formof their non-toxic pharmaceutically acceptable szflts. Such saltspossess the same order of activity as the free base, and are readilyprepared by reacting the base with an appropriate hydroxide or oxideand, accordingly, are included within the scope of this invention.Representative of such salts are the alkali metal salts, e.g., sodium,potassium and the like, and alkaline earth metal salts such asmagnesium, calcium and the like.

The hypolipidemic effective dosage of compounds (I) employed in thealleviation of lipidemia may vary depending on the particular compoundemployed and the severity of the condition being treated. However, ingeneral, satisfactory results are obtained when the compounds of formula(1) are administered at a daily dosage of from about 1.0 milligrams toabout 250 milligrams per kilogram of animal body weight, preferablygiven in divided doses two to four times a day, or in sustained releaseform. For most large mammals, the total daily dosage is from about 75milligrams to about 2500 milligrams. Dosage forms suitable for internaluse comprise from about 18.5 to about 1250 milligrams of the activecompound in intimate admixture with a solid or liqiud pharmaceuticallyacceptable carrier or diluent.

A representative formulation suitable for oral administration 2 to 4times a day for the treatment of lipidemia is a capsule prepared bystandard encapsulating techniques which contains the following:

Ingredients Weight (mg) ppivaloyl phenyl acetic acid 100 inert soliddiluent (starch, lactose, kaolin). 200

EXAMPLE I a-bromo-p-pivaloyl toluene To a suspension of 28.5 g (1.17 g.atoms) magnesium tumings in 150 ml tetrahydrofuran under a nitrogenatmosphere there is added ml (1.17 mole) of 4-bromotoluene in 650 ml drytetrahydrofuran, the

1% hours. The resulting Girgnard solution is added dropwise to a coldsolution of 128.0 g pivaloyl chloride (1.06 mole) in 500 ml drytetrahydrofuran at a rate that maintains the temperature at 0 to 5C. Thesolution is stirred for an additional 1% hours at 0 and then at roomtemperature for 18 hours. The mixture is then cooled to 0 and hydrolyzedby the addition of 100 ml 2N hydrochloric acid. The layers are separatedand 200 ml of ether is added to the organic phases which is then washedrespectively with 100 ml 2N hydrochloric acid, 100 ml. 10% sodiumbicarbonate solution and 100 ml saturated sodium chloride. The resultinglayer is dried over anhydrous sodium sulfate, filtered, and the solventis removed in vacuo to give p-pivaloyl toluene (b.p. 84C/0.7 mm,n=1.5l08). A mixture of 156.3 g. (0.886 mole) of the resulting p-pivaloyltoluene is then added to 157.8 g. (0.886 mole) N-bromosuccinimide, 4.0 g(0.016 mole) benzoyl peroxide and 150 ml. carbon tetrachloride andheated at reflux for 18 hours. The mixture is cooled with carbontetrachloride. The solvents are removed in vacuo and the resulting oilis distilled in vacuo to give a-bromo-p-pivaloyl toluene (hp 124 132/0.7mm, n =1.5546 V.P.C. 96% monobromo 4%-dibromo).

Following the above procedure and using in place of 4-bromotolueneequivalent amounts of:

a. 4-bromo-2-chlorotoluene,

b. 4-bromo-2-methoxytoluene,

c. 4-bromo-ethylbenzene, or

d. 4-bromo-2-fluorotoluene, there is obtained a.a-bromo-Z-chloro-4-pivaloyl toluene,

b. a-bromo-Z-methoxy-4-pivaloyl toluene,

c. a-bromo-a-methyl-4-pivaloyl toluene, or

d. a-bromo-2-fluoro-4-pivaloyl toluene, tively.

respecp-pivaloyl phenyl acetonitrile A solution of 34.3 g (0.700 mole)sodium cyanide in 40 ml of water is warmed to 50C and a solution ofa-bromo-p-pivaloyl toluene in ml ethanol is then added dropwise at sucha rate as to maintain the temperature at 50C. After the addition iscomplete the mixture is refluxed for four hours. The excess ethanol isremoved in vacuo and the resulting residue is treated with ether/water.The layers are separated and the ether is washed with cold 50% sulfuricacid, water and sodium bicarbonate, then the ether layer is dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo. Theresidue is distilled in vacuo to give p-pivaloyl phenyl acetonitrile(b.p. 143148C/0.75 mm n 1.5244).

Following the above procedure and using in place of a-bromo-p-pivaloyltoluene an equivalent amount of a. a-bromo-Z-chloro-4-pivaloyl toluene,

b. a-bromo-2-methoxy-4-pivaloyl toluene, or

c. a-bromo-a-methyl-4-pivaloyl toluene, or

d. a-bromo-2-fluoro-4-pivaloyl toluene, there is obtained a.2-chloro-4-pivaloyl phenyl acetonitrile,

b. 2-methoxy-4-pivaloyl phenyl acetonitrile,

c. 2-(p-pivaloyl phenyl) propionitrile, or

d. 2-fluoro-4-pivaloyl phenyl acetonitrile, respectively.

To a flask equipped with a stirrer, dropping funnel and condenser thereis added 50.0 g (0.25 mole) p-pivaloyl phenyl acetonitrile to 1 literconcentrated hydrochloric acid which is then refluxed for 48 hours. Theresultant precipitate is filtered. dissolved in chloroform. and washedwith 2N sodium hydroxide. The basic aqueous phase is separated from theorganic phase. cooled and acidified with concentrated hydrochloric acidand the resulting solid is then recrystallized from hot benzene to givep-pivaloyl phenyl acetic acid, m.p. (lll-l 12 C).

Following the above procedure and using in place of p-pivaloyl phenylacetonitrile an equivalent amount of a. 2-chloro-4-pivaloyl phenylacetonitrile.

c. 2-(p-pivaloy1 phenyl) propionitrile, or

d. 2-fluoro-4-pivaloyl phenyl acetonitrile, there is obtained a.2-chloro-4-pivaloyl phenyl acetic acid.

b. 2'(p-pivaloyl phenyl) propionic acid, or

d. 2-fluoro-4-pivaloyl phenyl acetic acid, respectively.

Again following the above procedure and using in place of p-pivaloylphenyl acetonitrile an equivalent amount of 2-methoxy-4-pivaloyl phenylacetonitrile in the presence of a dilute hyydrochloric acid in place ofconcentrated hydrochloric there is obtained 2-methoxy-4-pivaloyl phenylacetic acid.

The p-pivaloyl phenyl acetic acid of this example is an effectivehypolipidemic agent when orally administered to an animal suffering fromlipidemia at a dosage of from about 50 to 250 milligrams four times perday.

Z-methyl-Z-(p-pivaloyl phenyl) propionic acid To a suspension of 4.68 g.(0.12 mole) of sodium amide in 100 ml. of liquid ammonia at 78 C. thereis added dropwise for about 30 minutes a solution of 6.03 g. (0.03 mole)p-pivaloyl phenyl acetonitrile and 17 g. (0.12 mole) of methyl iodide in100 ml. of dry ether. The resulting mixture is stirred for 3 hours at 78C. and then there is added 6.5 g. of solid ammonium chloride, and theexcess ammonia is allowed to evaporate. Ether and water are added to theresidue and the layers are separated. The organic layer is washed withbrine. decolorized with charcoal, dried over anhydrous magnesiumsulfate, filtered and evaporated to give an oil. The crude oil isrefluxed with 100 ml. of 50% concentrated sulfuric acid for 72 hours.The resulting mixture is cooled and extracted with ether. The excessether is extracted with 2N sodium hydroxide, and the basic solution ischarcoaled, made acidic with concentrated hydrochloric acid andextracted with methylene chloride. The excess methylene chloride iswashed with brine, dried over anhydrous magnesium sulfate, filtered andevaporated. The residue is recrystallized from petroleum etherlether togive 2-methyl-2-(4-pivaloyl phenyl) propionic acid; m.p. l28- 130C.

Following the above procedure and using in place of p-pivaloyl phenylacetonitrile an equivalent amount of a. 2-chloro-4-pivaloyl phenylacetonitrile, or

b. 2-methoxy-4-pivaloyl phenyl acetonitrile, or

c. 2-fluoro-4-pivaloyl phenyl acetonitrile, there is obtained a,2-methyl-2(2-chloro-4-pivaloyl pionic acid,

b. 2-methyl-2-(2-methoxy'4-pivaloyl phenyl) propionic acid, or

c. 2-methly-2(2-fluoro-4-pivaloyl pionic acid, respectively.

What is claimed is:

l. A compound of the formula phenyl) prophenyl) proa c c0 11 CH3 lc R4where R, and R each independently, represent hydrogen,

or alkyl of l to 2 carbon atoms, and

R represents hydrogen, halo having an atomic weight of about 19 to 36 orstraight chain lower alkoxy, and

R and R each independently, represent alkyl having 1 or 2 carbon atomsor a pharmaceutically acceptable salt thereof.

2. A compound of the formula where R,, R and R are as defined in claim1, or a pharmaceutically acceptable salt thereof.

3. A compound of the formula where R, and R each represent the samelower alkyl,

9 10 5. The compound of claim 1 which is p-pivaloyl phenyl acetic acid.R 6. The compound of claim 1 which is 2-chloro-4- pivaloyl phenyl aceticacid. 5 7. The compound of claim 1 which is 2-fluoro-4- pivaloyl phenylacetic acid.

c=o 8. The compound of claim I which is Z-(p-pivaloyl CH -C-R phenyl)propionic acid.

I 9. The compound of claim 1 which is 2-methyl2- R5 (p-pivaloyl phenyl)propionic acid.

where R R and R are as defined in claim 1, or a pharmaceuticallyacceptable salt thereof.

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 beingbis-(N-methyl-p-toluenesulfonamido)-disulfide.
 3. The compound of claim1 being bis-(N-methyl-p-toluenesulfonamido)-sulfide.
 4. The compound ofclaim 1 being bis-(N-hexyl-benzenesulfonamido)-disulfide.
 5. Thecompound of claim 1 beingbis-(N-cyclohexyl-butanesulfonamido)-disulfide.
 6. The compound of claim1 being bis-(N-cyclohexyl-p-toluenesulfonamido)-sulfide.